Depression is thought to affect around twenty million Americans every year. The economic impact of depression is difficult to estimate, but reports indicate that approximately 30 billion dollars was lost directly and indirectly in 1990 as a result of the disease. Depression manifests itself in many different ways including persistent sad mood, loss of interest or pleasure in once enjoyable activities, significant change in appetite or body weight, sleep disorders, physical slowing or agitation, loss of energy, feelings of worthlessness, inappropriate guilt, difficulty thinking, difficulty concentrating, malaise, and recurrent thoughts of death or suicide. The families and friends of depressed individuals are often profoundly affected by the disease.
The present invention relates generally to depression. More specifically, the present invention relates to methods and materials used to isolate and detect a human depression predisposing gene, specifically the apoptotic protease activating factor 1 (APAF1) gene, some mutant alleles of which cause susceptibility to depression. More specifically, the invention relates to germline mutations in the APAF1 gene and their use in the diagnosis of predisposition to depression. The invention also relates to the prophylaxis and/or therapy of depression associated with a mutation in the APAF1 gene. The invention further relates to the screening of drugs for depression therapy. Finally, the invention relates to the screening of the APAF1 gene for mutations/alterations, which are useful for diagnosing the predisposition to depression.
Depression is typically diagnosed as major depressive disorder (unipolar major depression, bipolar disorder (manic-depressive illness), and dysthymic disorder (dysthymia). There are a number of subtypes of these major categories of depression. Diagnosis of these mental disorders is based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). American Psychiatric Association; Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), Washington, D.C., American Psychiatric Press, 1994.
Major depression is associated with low mood, low energy and motivation, insomnia, and feelings of worthlessness and hopelessness. Bipolar disorder is a severe psychiatric disorder that affects approximately 1% of the world's population (Goodwin, F. K. and Jameson, K. R. (1990) Manic-Depressive Illness, Oxford Univ. Press, New York). It is characterized by extreme swings in mood between mania and depression. Mania is accompanied by euphoria, grandiosity, increased energy, decreased need for sleep, rapid speech, and risk taking. Psychosis can occur in either state, and there is a 17% lifetime risk for suicide. Dysthymic disorder is considered a milder form of depression with symptom similar to that of major depression.
The etiology of depression is currently unknown, but epidemiological studies argue for a strong genetic component. Family studies indicate an approximately 7-fold increase in risk to first-degree family members (Tsuang, M. T. and Faraone, S. V. (1990) The Genetics of Mood Disorders, Johns Hopkins Univ. Press, Baltimore). Twin studies find an average 4-fold increase in risk to monozygotic vs. dizygotic twins. The mode of genetic transmission is unclear. Although some studies have supported the presence of autosomal dominant major loci (Spence, M. A. et al. (1995) Am. J. Med. Genet. 60:370-376; Rice, J. et al (1987) Arch. Gen. Psychiatry 44:441-447), it has also been argued that bipolar disorder is oligogenic with multiple loci of modest effect.
Although initial attempts at linkage studies met with inconsistent replication (Egeland, J. A. et al. (1987) Nature 325:783-787; Kelsoe, J. R. et al. (1989) Nature 342:238-243; Baron, M. et al. (1987) Nature 326:289-292; Baron, M. (1991) Soc. Biol. 38:179-188), more recently, the accumulation of multiple studies of larger family sets has led to the reproducible identification of several genetic loci associated with depression. These include 4p, 12q, 13q, 18, 21q, and Xq among others (Blackwood, D. H. et al. (1996) Nat. Genet. 12:427-430; Dawson, E. et al. (1995) Am. J. Med. Genet. 60:94-102; Detera-Wadleigh, S. D. et al. (1999) Proc. Natl. Acad. Sci. USA 96:5604-5609; Berrettini, W. H. et al. (1994) Proc. Natl. Acad. Sci. USA 91:5918-5921; Freimer, N. B. et al. (1996) Nat. Genet. 12:436-441; Straub, R. E. et al. (1994) Nat. Genet. 8:291-296; Pekkarinen, P. et al. (1995) Genome Res. 5:105-115; Craddock, N. & Jones, I. (1999) J. Med. Genet. 36:585-594; Craddock, N. & Jones, I. (2001) Br. J. Psychiatry 41:s128-s133). Linkage between bipolar disorder and chromosome 12q23-12q24 has been reported (Green, E. K. et al. (2000) Am. J. Med. Genet. 96:545; Morissette, J. et al. (1999) Am. J. Med. Genet. 88: 567-587; Ewald, H. et al. (1998) Psychiatr. Genet. 8:131-140 (1998); Degan, B. et al. (2001) Mol. Psychiatry 6:450-455; Detera-Wadleigh, S. D. et al. (1999) Am. J. Med. Genet. 88:255-259; Jacobsen, N. et al. (1996) Psych. Genet. 6:195-199; Rice, J. P. et al. (1997) Am. J. Med. Genet. 74:247-253).
In view of the importance of early diagnosis of depression, there is a need to identify genes associated with depression for diagnostic and therapeutic purposes.